J. CHEM. SOC. PERKIN TRANS. I 1989 Partial Synthesis and the Absolute Configuration of Two New Gelsemiurn Alkaloids, Koumidine and (192)-Taberpsychine Hiromitsu Takayama, Mariko Kitajima, Sumphan Wongseripipatana, and Shin-ichiro Sakai * Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Ya yoi-cho, Chiba 260,Japan The stereoselective transformation of ajmaline (3)into a new Gelsemium alkaloid, (19Z)-taber-psychine (I), via koumidine (2) is described. Recently we elucidated the structure of a minor Gelsemiurn alkaloid, (192)-taberpsychine (1) and revised the structure of koumidine (2) by spectroscopic analysis.' These alkaloids possess an unusual (192) ethylidene side chain compared with that of the conventional sarpagine class of indole alkaloids.2 In order both to provide support for the spectroscopic assignments and to determine the absolute configurations of these compounds we have synthesized them from ajmaline (3)3 (Scheme 1).The transformation involves mainly two (2) (3) Scheme 1. structural changes of the starting material (3):(i) stereoselective introduction of a 19,20 double bond and (ii) an indoline to indole transformation without epimerization at C-16. In order to liberate the masked aldehyde (C-21) from the amino acetal function and to protect the N, group as carbamate, ajmaline (3) was successively treated with N,N-dimethylhydrazine and a catalytic amount of H2S04, methyl chloroformate in 1~ NaOH-CH,Cl,, and then CuC12 in aqueous THF (pH 7), to afford the aldehyde (4) in 60% overall yield (Scheme 2).Attempts at the direct conversion of (3) into (4) by the reaction with chloroformates gave the carbonate (21- OC0,R) derivatives. After the protection of the 17-hydroxy group as a methoxyethoxymethyl (MEM) ether, bromine was introduced at the 20 position uia the t-butyldimethylsilyl (TBS) enol ether. Treatment of (5) with 1,8-diazabicyclo[5.4.O]undec-7-ene (DBU) in DMF gave the desired (192) olefin (6) in 60% yield, selectively [(6) :(7)= 5 :13. The geometry of the olefins (6) and (7) was unambiguously determined by n.0.e. experiments.? The major a,a-unsaturated aldehyde (6) was reduced with NaBH, and then ring closure between C-21 and N, was t Irradiation of the 18-methyl protons (6 2.14) in (6)led to enhancement (17%) of the C-21 aldehyde proton (6 10.2),while 25% enhancement was observed between the C-19 olefinic proton (6 6.50) and (2-21 aldehyde proton (6 9.33) in (7).Ji-iv OMEM OMEM Me Me (6) Z 21 CHO ORq&Me \ 19 (8) 19-(Z), R=MEM (13) R=TBSxiL (9) 19-(Z), R=H (14) R=TMS r (10) 19-(€), R=H (11) 19-(Z), R=TBS / ( i5 I R'=CHO, R~=H ( 16I R'=H, R~=CHOH ( 2 ) R'= CH,OH, $2H Scheme 2. Rcqynrs and conditions: i, N,N-Dimethylhydrazine, cat. H,SO,, 3A molecular sieves, dry EtOH, reflux, 5 h; ii, methyl chloroformate, 1~ NaOH, CH,CI,, O0C, 40 min., 79% from (3); iii, CuCl,, THF-H,O, phosphate buffer, r.t., overnight, 75%; iv, MEM chloride, di-isopropyl(ethyl)amine, dry CH,CI,, reflux, 4.5 h, 81x;v, TBS-trifluoromethanesulphonate, Et,N,dryCH,Cl,,O OC,2.5h, 71"/,;vi, N-bromosuccinimide, dry THF, -15 "C, 30 min, 76%; vii, DBU, dry DMF, r.t.overnight, (6)60%,(7)12%; viii, NaBH,, MeOH, r.t., 88%; ix, NaOH, ethylene glycol, H,O, reflux, 1 h, 87%; x, methane-sulphonylchloride, pyridine, r.t., 30 min, 62%; xi, conc. HCl, MeOH, reflux, 5 h, 95%; xii, TBS-trifluoromethanesulphonate, Et,N, dry CH,CI,, 0 OC, 1 h, 80%; xiii, Pb(OAc),, dry CH,CI,, -70 *C to minus 10 "C, (13) 59%, (14) 48% from (9) t'iu (12); xiv, TMS-trifluoromethane-sulphonate, Et,N, dry CH,CI,, 0°C; xv, Bu,NF, THF, r.t. 15 min; xvi, AcOH-THF-H,O (3: 1:l), r.t., 30min; xvii, NaBH,, MeOH, r.t. 30 min, (16) 60% from (13), (2) 70% from (14); xviii, methyl chloroformate, MgO, THF-H,O, r.t., 1.5 h; xix, LiAlH,, THF, r.t., 1.5 h, 30% from (2) performed by successive treatment of the resulting alcohol with NaOH in aqueous ethylene glycol and methanesulphonyl chloride in pyridine to afford the deoxyajmaline derivative (8).A similar sequential reduction (removal of the protective group in N,, ring closure, and deprotection of the 17-hydroxy group), of the minor E olefin (7) gave tetraphyllicine The indoline to indole transformation for (13) was accomplished by deprotection of the 17-hydroxy group. Tn order to prevent epimerization at C-16 during this process, mild removal of the protective group was required. Since the MEM ether utilized in earlier stages in this transformation could not be cleanly removed by the reported procedure,6 we substituted the MEM group with TBS ether.We then prepared the indolenine (13) by lead tetra-acetate oxidation' of (11). After deprotection of the TBS ether in (13) by the use of tetra- butylammonium fluoride in THF at room temperature, the resulting aldehyde (15) was immediately reduced with NaBH, in MeOH to afford, however, surprisingly 16-epi-koumidine (16) [(19Z)-normacusine B, m.p. 169-173 "C] as the sole product. The same result was obtained by use of AcOH-THF- H,O (at 70 "C)for the deprotection of TBS group instead of F-. The epimerization at C-16 could be prevented by use of the trimethylsilyl (TMS) group in place of the TBS ether. Thus, the indolenine (14), which was unstable both to work-up in the customary manner and column chromatography, was treated with AcOH-THF-H,O (at room temp.) and then reduced with NaBH, in MeOH to yield koumidine (2), [cc]k3 -23.8" (c 0.6, MeOH), in 70% overall yield form (14).The 'H n.m.r., i.r., and mass spectra and m.p. (202-204 "C) were identical with those of natural koumidine (2), [a];' -20.8" (c 1.8, MeOH). * Direct comparison of synthetic (lo), m.p. 296296 OC, [XI'," + 16" (c. 0.4, pyridine), with the authentic sample sent by Prof. P. J. Scheuer, established the identity in all respects (t.l.c., mixed m.p., and ir., 'H n.m.r., and mass spectra). J. CHEM. SOC. PERKIN TRANS. I 1989 Koumidine (2) was treated with methyl chloroformate in THF-H20 in the presence of MgO and the resulting carbamate was reduced with lithium aluminium hydride to furnish (192)- taberpsychine (l),[K]$,~ -151" (c 0.3, CHCl,), in 30% overall yield from (2).The synthetic compound exhibited spectral properties ('H n.m.r., i.r., u.v., and mass) in accord with those of an authentic sample, [x]k3 -180" (c 0.4, CHCI,). Acknowledgements We thank Professor P. J. Scheuer, University of Hawaii, for providing a sample of natural tetraphyllicine. References 1 D. Ponglux, S. Wongseripipatana, S. Subhadhirasakul, H. Takayama, M. Yokota, K. Ogata, C. Phisalaphong, N. Aimi, and S. Sakai, Tetrahedron, 1988,44,5075. 2 W. I. Taylor, 'The Alkaloids,' ed. by R. H. F. Manske, Academic Press, New York, 1968, vol. XI, ch. 2. 3 Total syntheses and the absolute configuration of ajmaline were established: (a)S. Masamune, S. K. Ang, C. Egli, N. Nakatsuka, S. K. Sarkar, and Y. Yasunari, J. Am. Chem. SOC.,1967,89,2506; (h) L. K. Oliver and E. E. van Tamelen, ibid., 1970,92,2136; (c) M. F. Bartlett, R. Sklar, W. I. Taylor, E. Schlittler, R. L. S. Amai, P. Beak, N. V. Bringi, and E. Wenkert, ibid.,1962,84,622. 4 E. J. Corey and S. Knapp, Tetruhedron Lett., 1976,3667. 5 P. J. Scheuer, M. Y. Chang, and H. Fukami, J. Org. Chem., 1963,28, 2641. 6 (a)E. J. Corey, J-L. Gras, and P. Ulrich, Tetrahedron Lett., 1976, 809; (b) S. Hanessian, D. Delorme, and Y. Dufresne, Tetrahedron Lett., 1984,25,25 15. 7 M. F. Bartlett, B. F. Lambert, and W. I. Taylor, J. Am. Chem. SOC., 1964,86,729. Received 17th October 1988 (Accepted 19th January 1989); Paper 9/00305C
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